Department of Pediatric Nephrology and Solid Organ Transplantation, University Hospitals Leuven, Belgium.
Int J Pharm. 2013 Aug 16;452(1-2):14-35. doi: 10.1016/j.ijpharm.2013.05.033. Epub 2013 May 24.
Since their introduction circa 35 years ago, calcineurin-inhibitors (CNI) have become the cornerstone of immunosuppressive therapy in solid organ transplantation. However, CNI's possess a narrow therapeutic index with potential severe consequences of drug under- or overexposure. This demands a meticulous policy of Therapeutic Drug Monitoring (TDM) to optimize outcome. In clinical practice optimal dosing is difficult to achieve due to important inter- and intraindividual variation in CNI pharmacokinetics. A complex and often interdependent set of factors appears relevant in determining drug exposure. These include recipient characteristics such as age, race, body composition, organ function, and food intake, but also graft-related characteristics such as: size, donor-age, and time after transplantation can be important. Fundamental (in vitro) and clinical studies have pointed out the intrinsic relation between the aforementioned variables and the functional capacity of enzymes and transporters involved in CNI metabolism, primarily located in intestine, liver and kidney. Commonly occurring polymorphisms in genes responsible for CNI metabolism (CYP3A4, CYP3A5, CYP3A7, PXR, POR, ABCB1 (P-gp) and possibly UGT) are able to explain an important part of interindividual variability. In particular, a highly prevalent SNP in CYP3A5 has proven to be an important determinant of CNI dose requirements and drug-dose-interactions. In addition, a discrepancy in genotype between graft and receptor has to be taken into account. Furthermore, common phenomena in solid organ transplantation such as inflammation, ischemia- reperfusion injury, graft function, co-medication, altered food intake and intestinal motility can have a differential effect on the expression enzymes and transporters involved in CNI metabolism. Notwithstanding the built-up knowledge, predicting individual CNI pharmacokinetics and dose requirements on the basis of current clinical and experimental data remains a challenge.
自 35 年前问世以来，钙调磷酸酶抑制剂（CNI）已成为实体器官移植中免疫抑制治疗的基石。然而，CNI 的治疗指数较窄，药物暴露不足或过量可能会产生严重后果。这需要进行精细的治疗药物监测（TDM）策略，以优化治疗效果。在临床实践中，由于 CNI 药代动力学存在重要的个体内和个体间差异，因此很难实现最佳剂量。一套复杂且相互关联的因素似乎与确定药物暴露有关。这些因素包括患者的特征，如年龄、种族、身体成分、器官功能和饮食摄入，但也包括移植物的特征，如：大小、供体年龄和移植后的时间等，这些因素都可能很重要。基础（体外）和临床研究指出了上述变量与参与 CNI 代谢的酶和转运体的功能能力之间的内在关系，这些酶和转运体主要位于肠道、肝脏和肾脏。负责 CNI 代谢的基因（CYP3A4、CYP3A5、CYP3A7、PXR、POR、ABCB1（P-gp）和可能的 UGT）中常见的多态性能够解释个体间变异性的重要部分。特别是，CYP3A5 中的一个高度常见的 SNP 已被证明是 CNI 剂量需求和药物剂量相互作用的重要决定因素。此外，还需要考虑移植物和受体之间的基因型差异。此外，实体器官移植中的常见现象，如炎症、缺血再灌注损伤、移植物功能、联合用药、饮食摄入和肠道动力改变，可能会对参与 CNI 代谢的酶和转运体的表达产生不同的影响。尽管已经有了这些知识，但基于当前的临床和实验数据来预测个体 CNI 药代动力学和剂量需求仍然是一个挑战。
